This invention relates to novel hygromycin derivatives that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
Hygromycin A is a fermentation-derived natural product first isolated from Streptomyces hygroscopicus in 1953. As an antibiotic, hygromycin A possesses activity against human pathogens and is reported to possess potent in vitro activity against Serpulina (Treponema) hyodysentetiae which causes swine dysentery. Several references refer to semisynthetic modifications of hygromycin A, including the following: derivatization of the 5xe2x80x3 ketone of hygromycin A to the 2,4-dinitrophenylhydrazone is referred to in K. Isono et al., J. Antibiotics 1957, 10, 21, and R. L. Mann and D. O. Woolf, J. Amer Chem. Soc. 1957, 79, 120. K. Isono et al., ibid., also refer to the thiosemicarbazone at 5xe2x80x3; reduction of the 5xe2x80x3 ketone of hygromycin A to the 5xe2x80x3 alcohol is referred to in R. L. Mann and D. O. Woolf, ibid., as well as in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 533 and S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1993, 3, 295; furanose analogues are referred to in B. H. Jaynes et al., Bioorg. Med. Chem. Lett. 1993, 3, 1531, and B. H. Jaynes et al., J. Antibiot. 1992, 45, 1705; aromatic ring analogues are referred to in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1993, 3, 289, and C. B. Cooper et al., Bioorg. Med. Chem. Lett. 1997, 7, 1747; enamide analogues are referred to in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 533; aminocyclitol analogues are referred to in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 1015, and in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 1043. The hygromycin A derivatives of the present invention possess broad activity against both gram-negative and gram-positive bacteria and protozoa. WO 99/012941, published Sep. 14, 1999, refers to the treatment of bacterial infections by co-adminstering hygromycin and/or epihygromycin with a pyridone carboxylic acid antibacterial compound such as tosufloxacin, nalidixic acid, piromidic acid cinoxacin and/or enoxacin. Hygromycin derivatives are also described and claimed in U.S. provisional patent application Ser. No. 60/110,618 (filed Dec. 2, 1998), U.S. patent application Ser. No. 09/380,718 (filed Apr. 8, 1999), and PCT international patent application number PCT/IB99/00795 (filed May 13, 1999). The foregoing United States and PCT applications are incorporated herein by reference in their entirety.
The present invention relates to compounds of the formula 
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
X is H, F, OH, or NH2;
Y is O or CH2;
Z1 is R3 and Z2 is OR13; or Z1 is H and Z2 is R3, xe2x80x94NR3R4, xe2x80x94NR3C(O)R4 or F;
or Z1 and Z2 are taken together to form xe2x95x90O or xe2x95x90NOR3;
W1 is R3 and W2 is OR13; or W1 is H and W2 is R3, xe2x80x94NR3R4, xe2x80x94NR3C(O)R4, or F;
or W1 and W2 are taken together to form xe2x95x90O or xe2x95x90NOR3;
V is a group having the following structure 
or V is R3OC(O)xe2x80x94, R3R4NC(O)xe2x80x94 or R3O(R4)NC(O)xe2x80x94, in which groups R3 and R4 optionally can be taken together to form a 4 to 10 membered heterocyclic group which may be optionally substituted by 1 to 3 R6 groups;
or V is a group having the following structure: 
or V is a group of the structure 
xe2x80x83where both E and Z isomers are included;
or V is a carbon-linked 4 to 10 membered heterocyclic group, which may be optionally substituted by 1 to 3 R6 groups;
R1 is H and R2 is xe2x80x94NR3R4, xe2x80x94NR4C(O)R3, xe2x80x94OC(O)NR3R4 or xe2x80x94OR3;
or R1 and R2 are taken together to form O, xe2x95x90Nxe2x80x94OR3, or xe2x95x90C(R5)X1xe2x80x94X2xe2x80x94R8, wherein:
X1 is xe2x80x94CR9R10xe2x80x94, and X2 is selected from xe2x80x94CR9R10xe2x80x94, xe2x80x94S(O)nxe2x80x94 wherein n is an integer from 0 to 2, xe2x80x94NR9xe2x80x94, and O; where X2 is xe2x80x94NR9xe2x80x94, then R8 and R9 may be taken together to form a 5 to 12 membered heterocyclic group, which is optionally substituted by 1 to 3 R6 groups; or X1 and X2 independently or together represent a bond with the proviso that if X1 is a bond than X2 is either a bond or xe2x80x94CR9R10xe2x80x94;
each R3 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR9R10)t(C3-C10 cycloalkyl), xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer from 0 to 5, said alkyl, alkenyl and alkynyl groups optionally contain 1 or 2 hetero moieties selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer from 0 to 2, and xe2x80x94N(R9)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other, and the proviso that an O atom, a S atom or a N atom are not attached directly to a triple bond or non-aromatic double bond; said cycloalkyl, aryl and heterocyclic R3 groups are optionally fused to a benzene ring, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; the xe2x80x94(CR9R10)txe2x80x94 moieties of the foregoing R3 groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 5; and the foregoing R3 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 must be attached through a carbon atom unless R3is H;
each R4 is independently H or C1-C10 alkyl;
R5 is H or C1-C6 alkyl, wherein the foregoing R5 alkyl group is optionally substituted by 1 or 2 R6 groups
each R6 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94C(O)OR7, xe2x80x94NR9C(O)OR11, xe2x80x94OC(O)R7, xe2x80x94NR9SO2R11, xe2x80x94SO2N7R9, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94S(O)j(CR9R10)m(C6-C10 aryl), xe2x80x94S(O)j(C1-C6 alkyl), wherein j is an integer from 0 to 2, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), xe2x80x94NR9(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 4; said alkyl, alkenyl and alkynyl groups optionally contain 1 or 2 hetero moieties selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer from 0 to 2, and xe2x80x94N(R7)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other, and the proviso that an O atom, a S atom or a N atom are not attached directly to a triple bond or a non-aromatic double bond; said cycloalkyl, aryl and heterocyclic R6 groups are optionally fused to a C6-C10 aryl group, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and said alkyl, cycloalkyl, aryl and heterocyclic R groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, xe2x80x94NR9SO2R11, xe2x80x94SO2NR7R9, xe2x80x94C(O)R7, xe2x80x94C(O)OR7, xe2x80x94OC(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94OR7, C1-C10 alkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 4;
each R7 is independently selected from H, C1-C10 alkyl, C3-C10 cycloalkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 4; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer ranging from 0 to 2, and xe2x80x94N(R9)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said cycloalkyl, aryl and heterocyclic R7 groups are optionally fused to a C6-C10 aryl group, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the foregoing R7 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, xe2x80x94C(O)R9, xe2x80x94C(O)OR9, xe2x80x94OC(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy, and with the proviso that R7 must be attached through a carbon atom unless R7 is H;
each R8 is independently selected from R3, xe2x80x94C(O)R3, or xe2x80x94C(O)NR9R3, wherein R3 is as defined above;
each R9 and R10 is independently H or C1-C6 alkyl; and,
R11 is selected from the substituents provided in the definition of R7 except H.
R12 is selected from the substituents provided in the definition of R3, except that R12 cannot be methyl if (a) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is xcex2-OH; or (b) if X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 and Z2 are both H; and with the proviso that R12 must be attached through a carbon atom unless R12 is H;
R13 is defined as described for R3; and,
R14 is H or C1-C10 alkyl, except that R14 cannot be H when R13 is H.
In a first preferred embodiment of the compound of formula 1:
V equals 
xe2x80x83and the preferred configuration of the 1xe2x80x3 center is that of hygromycin A
In a second preferred embodiment of the compound of formula 1:
V is as indicated in the first preferred embodiment above, but R1 and R2 are taken together as xe2x95x90O or xe2x95x90NOR3.
In a third preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the second preferred embodiment, but:
Z1 is R3 and Z2 is OR13; or Z1 is H and Z2 is R3, xe2x80x94NR3R4, xe2x80x94NR3C(O)R4, or F; and W1 is R3 and W2 is OR13; or W1 is H and W2 is R3, xe2x80x94NR3R4, xe2x80x94NR3C(O)R4, or F; wherein each R3 and R13 are independently selected from H, C1-C4 alkyl, xe2x80x94(CR9R10)t(C3-C10 cycloalkyl), xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer from 0 to 3, said alkyl group optionally contains 1 hetero moiety selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer from 0 to 2, and xe2x80x94N(R9)xe2x80x94, and the foregoing R3 and R13 groups, except H, are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 and R13 must be attached through a carbon atom unless it is H; each R4 is independently H or C1-C4 alkyl; each R6 is independently selected from C1-C4 alkyl, oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9; wherein R7 and R9 are H, C1-C4 alkyl; R11 is C1-C4 alkyl.
R1 and R2 are taken together as xe2x95x90O or xe2x95x90NOR3, wherein each R3 is independently selected from C1-C4 alkyl, C3-C8 alkenyl, xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer ranging from 0 to 3, said alkyl and alkenyl groups optionally contain 1 or 2 hetero moieties selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer ranging from 0 to 2 and xe2x80x94N(R9)xe2x80x94, with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other, and the proviso that an O atom, a S atom or a N atom are not attached directly to a non-aromatic double bond; said aryl and heterocyclic R3 groups are optionally fused to a benzene ring, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the foregoing R3 groups, including any optional fused rings referred to above, are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 must be attached through a carbon atom; R12 is C1-C4 alkyl, and said alkyl group is optionally substituted by 1 to 3 R6 groups, except that R12 cannot be methyl if (a) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is xcex2-OH, or if (b) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is H; each R6 is independently selected from C1-C4 alkyl, oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9SO2R11, xe2x80x94SO2NR7R9, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94S(O)j(CR9R10)m(C6-C10 aryl), xe2x80x94S(O)j(C1-C6 alkyl), wherein j is an integer ranging from 0 to 2, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), xe2x80x94NR9(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 2; and said alkyl, cycloalkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94NR9SO2R11, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94OR7, C1-C4 alkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 2; R7 is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 2; said alkyl group optionally includes 1 hetero moiety selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer from 0 to 2, and xe2x80x94N(R9)xe2x80x94; said cycloalkyl, aryl and heterocyclic R7 groups are optionally fused to a C6-C10 aryl group, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the foregoing R7 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy, and with the proviso that R7 must be attached through a carbon atom unless R7 is H; R9 and R10 are independently H, C1-C4 alkyl; R11 is selected from R7 except H.
In a fourth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the third preferred embodiment, but:
X is F, H or OH;
Y is O;
W1 is R3, w2 is OR13; or W1 is H, W2 is R3 or F; Z1 is R3, Z2 is OR13; or Z1 is H, Z2 is R3 or F; wherein R3 and R13 are independently H, C1-C4 alkyl, and said alkyl groups are optionally substituted by 1 to 3 R6 groups; wherein each R6 is independently oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, or xe2x80x94NR7R9; wherein R7 and R9 are H or C1-C4 alkyl; R11 is C1-C4 alkyl;
R1 and R2 are taken together as xe2x95x90NOR3, R3 is xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer from 0 to 3; the foregoing R3 groups are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 must be attached through a carbon atom; R12 is C1-C4 alkyl, and said alkyl group is optionally substituted by 1 to 3 R6groups, except that R12 cannot be methyl if (a) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is xcex2-OH, or if (b) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is H; wherein R6 is C1-C4 alkyl, oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), xe2x80x94NR9(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 2; said alkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94NR9SO2R11, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94OR7, and C1-C4 alkyl;
R7 is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; the foregoing R7 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy; each R9 and R10 are independently H or C1-C4 alkyl; R11 is selected from R7 except H.
In a fifth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the fourth preferred embodiment, but:
Z1 is H, Z2 is OH; or Z1 is methyl, Z2 is OH; or both Z1 and Z2 are H; or Z, is H, Z2 is F;
W1 is H, W2 is OH;
R1 and R2 are taken together as xe2x95x90NOR3, wherein R3 is xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer ranging from 0 to 2, and the foregoing R3 groups are optionally substituted by 1 to 5 R6 groups; wherein R6 is C1-C4 alkyl, oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; said alkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94OR7, and C1-C4 alkyl;
R7 is independently selected from H, C1-C4 alkyl; the foregoing R7 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from trifluoromethyl, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R11, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, and C1-C4 alkoxy; R9 and R10 are independently H, C1-C4 alkyl; R11 is selected from R7 except H; R12 is C1-C4 alkyl except that R12 cannot be methyl if (a) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is xcex2-OH, or if (b) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is H.
In a sixth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the fifth preferred embodiment, but:
R1 and R2 are taken together as xe2x95x90NOR3, wherein R3 is xe2x80x94(CR9R10)t-phenyl, and xe2x80x94(CR9R10)t(5 to 9 membered heterocyclic), where t is 0 or 1, and the foregoing R3 groups are optionally substituted by 1 to 5 R6 groups, wherein each R6 is independently C1-C4 alkyl, halo, trifluoromethyl, and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 1; said heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from halo, trifluoromethyl, and C1-C4 alkyl; each R9 and R10 is independently H or C1-C3 alkyl.
In a seventh preferred embodiment of the compound of formula 1: 
and R1 and R2 are taken together as xe2x95x90C(R5)X1xe2x80x94X2xe2x80x94R8 and the preferred configuration of the 1xe2x80x3 center is that of hygromycin A.
In an eighth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the seventh preferred embodiment, but:
W1 is R3, W2 is OR13; or W1 is H, W2 is R3, NR3R4, NR3C(O)R4, or F; Z1 is R3, Z2 is OR13; or Z1 is H, Z2 is R3, NR3R4, NR3C(O)R4, or F; wherein R3 and R13 are independently selected from H, C1-C4 alkyl, xe2x80x94(CR9R10)t(C3-C10 cycloalkyl), xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer ranging from 0 to 3, said alkyl group optionally contains 1 hetero moiety selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer ranging from 0 to 2, and xe2x80x94N(R9)xe2x80x94, and the foregoing R3 and R13 groups, except H, are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 and R13 must be attached through a carbon atom unless it is H; each R4 is independently H or C1-C4 alkyl; each R6 is independently selected from C1-C4 alkyl, oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, and xe2x80x94NR7R9; wherein each R7 and R9 is independently H or C1-C4 alkyl; R11 is C1-C4 alkyl;
R1 and R2 are taken together as xe2x95x90C(R5)X1xe2x80x94X2xe2x80x94R8; wherein X1 is xe2x80x94CR9R10xe2x80x94, and X2 is selected from xe2x80x94CR9R10xe2x80x94, xe2x80x94S(O)nxe2x80x94 wherein n is 0 to 2, xe2x80x94NR9xe2x80x94, and O; where X2 is xe2x80x94NR9xe2x80x94, then R8 and R9 may be taken together to form a 5 to 12 membered heterocyclic, which is optionally substituted by 1 to 3 R6 groups; X1 and X2 can also independently or together represent a bond with the proviso that if X1 is a bond than X2 must be either a bond or xe2x80x94CR9R10xe2x80x94;
and where R5 is H or C1-C6 alkyl, wherein the foregoing R5 alkyl group is optionally substituted by 1 or 2 R6 groups:
and where each R8 is independently selected from R3, xe2x80x94C(O)R3, or xe2x80x94C(O)NR9R3, with the additional proviso that an N and O atom, and an N and S atom are not attached directly to each other, wherein each R3 is independently selected from C1-C4 alkyl, C3-C8 alkenyl, xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer ranging from 0 to 3, said alkyl or alkenyl group optionally contains 1 hetero moiety selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer ranging from 0 to 2, and xe2x80x94N(R9)xe2x80x94, with the proviso that an O atom, a S atom or a N atom are not attached directly to a non-aromatic double bond; said aryl and heterocyclic R3 groups are optionally fused to a benzene ring, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the foregoing R3 groups, including any optional fused rings referred to above, are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 must be attached through a carbon atom; R12 is C1-C4 alkyl, and said alkyl group is optionally substituted by 1 to 3 R6 groups, except that R12 cannot be methyl if (a) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is xcex2-OH, or if (b) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is H; each R6 is independently selected from C1-C4 alkyl, oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9SO2R11, xe2x80x94SO2NR7R9, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94S(O)j(CR9R10)m(C6-C10 aryl), xe2x80x94S(O)j(C1-C6 alkyl), wherein j is an integer ranging from 0 to 2, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), xe2x80x94NR9(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; and said alkyl, cycloalkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94NR9SO2R11, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94OR7, C1-C4 alkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; R7 is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; said alkyl group optionally includes 1 hetero moiety selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer ranging from 0 to 2, and xe2x80x94N(R9)xe2x80x94; said cycloalkyl, aryl and heterocyclic R7 groups are optionally fused to a C6-C10 aryl group, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the foregoing R1 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy, and with the proviso that R7 must be attached through a carbon atom unless R7is H; each R9 and R10 are independently H or C1-C4 alkyl; R11 is selected from R7 except H.
In a ninth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the eighth preferred embodiment, but:
X is F, H or OH;
Y is O;
W1 is R3, W2 is OR13; or W1 is H, W2 is R3, NR3R4, or F; Z1 is R3, Z2 is OR13; or Z1 is H, Z2 is R3, NR3R4, or F; wherein each R3 and R13 are independently H or C1-C4 alkyl, and said alkyl groups are optionally substituted by 1 to 3 R6 groups; wherein each R6 is independently oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, and xe2x80x94NR7R9; wherein each R7 and R9 is independently H or C1-C4 alkyl; R11 is C1-C4 alkyl;
R1 and R2 are taken together as xe2x95x90C(R5)X1xe2x80x94X2xe2x80x94R8; wherein X1 is xe2x80x94CR9R10xe2x80x94, and X2 is selected from xe2x80x94CR9R10xe2x80x94, xe2x80x94S(O)nxe2x80x94 wherein n is 0 to 2, xe2x80x94NR9xe2x80x94, and O; where X2 is xe2x80x94NR9xe2x80x94, then R8 and R9 may be taken together to form a 5 to 12 membered heterocyclic, which is optionally substituted by 1 to 3 R6 groups; X1 and X2 can also independently or together represent a bond with the proviso that if X1 is a bond than X2 must be either a bond or xe2x80x94CR9R10xe2x80x94;
and where R5 is H or C1-C6 alkyl, wherein the foregoing R5 alkyl group is optionally substituted by 1 or 2 R6 groups:
and where R8 is R3 wherein each R3 is independently xe2x80x94(CR9R10)t(C6-C10 aryl) or xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer ranging from 0 to 3; the foregoing R3 groups are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 must be attached through a carbon atom; R12 is C1-C4 alkyl, and said alkyl group is optionally substituted by 1 to 3 R6 groups, except that R12 cannot be methyl if (a) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is xcex2-OH, or if (b) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is H; wherein each R6 is independently C1-C4 alkyl, oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), xe2x80x94NR9(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; said alkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94NR9SO2R11, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94OR7, and C1-C4 alkyl;
each R7 is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; the foregoing R7 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy; each R9 and R10 are independently H or C1-C4 alkyl; R11 is selected from R7 except H.
In a tenth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the ninth preferred embodiment, but:
Z1 is H, Z2 is OH; or Z1 is methyl, Z2 is OH; or Z1 is H, Z2 is NH2; or both Z1 and Z2 are H; or Z1 is H, Z2 is F;
W1 is H, W2 is OH;
R1 and R2 are taken together as xe2x95x90C(R5)X1xe2x80x94X2xe2x80x94R8; wherein X1 is xe2x80x94CH2xe2x80x94, and X2 is selected from xe2x80x94S(O)nxe2x80x94 wherein n is 0 to 2, xe2x80x94NR9xe2x80x94, and O; where X2 is xe2x80x94NR9xe2x80x94, then R8 and R9 may be taken together to form a 5 to 12 membered heterocyclic, which is optionally substituted by 1 to 3 R6 groups;
and where R5 is H or C1-C6 alkyl, wherein the foregoing R5 alkyl group is optionally substituted by 1 or 2 R6 groups:
and where R8 is R3, wherein R3 is xe2x80x94(CH2)t(C6-C10 aryl) or xe2x80x94(CH2)t(4 to 10 membered heterocyclic), wherein each t is independently an integer from 0 to 2, and the foregoing R3 groups are optionally substituted by 1 to 5 R6 groups; wherein each R6 is independently C1-C4 alkyl, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94(CH2)m(C6-C10 aryl), xe2x80x94O(CH2)m(C6-C10 aryl), and xe2x80x94(CH2)m(4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 2; said alkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94OR7, and C1-C4 alkyl;
each R7 is independently selected from H and C1-C4 alkyl; the foregoing R7 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from oxo, trifluoromethyl, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, and C1-C4 alkoxy; each R9 and R10 are independently H, C1-C4 alkyl; R11 is selected from R7 except H; R12 is C1-C4 alkyl except that R12 cannot be methyl if (a) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is xcex2-OH, or if (b) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is H.
In an eleventh preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the tenth preferred embodiment, but:
R1 and R2 are taken together as xe2x95x90C(R5)X1xe2x80x94X2xe2x80x94R8; wherein R5 is H, X1 is xe2x80x94CH2xe2x80x94, and X2 is O, and wherein R8 is R3, wherein R3 is phenyl or (5 to 6 membered heterocyclic), and the foregoing Re groups are optionally substituted by 1 to 5 R6 groups, wherein each R6 is independently selected from C1-C4 alkyl, halo, trifluoromethyl, and xe2x80x94(CH2)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 1; said heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from halo, trifluoromethyl, and C1-C4 alkyl.
In a twelfth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the first preferred embodiment, but:
R1 is H and R2 is xe2x80x94NR3R4, xe2x80x94NR4C(O)R3, xe2x80x94OC(O)NR3R4 or xe2x80x94OR3 and the preferred configuration of the 1xe2x80x3 center is that of hygromycin A.
In a thirteenth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the twelfth preferred embodiment, but:
X is F, H or OH;
Y is O;
W1 is R3, W2 is OR13; or W1 is H, W2 is R3 or F; Z1 is R3, Z2 is OR13; or Z1 is H, Z2 is R3 or F; wherein each R3 and R13 are independently H or C1-C4 alkyl, and said alkyl groups are optionally substituted by 1 to 3 R6 groups; wherein each R6 is independently halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, or xe2x80x94NR7R9; wherein each R7 and R9 are independently H or C1-C4 alkyl; R11 is C1-C4 alkyl;
and in the substituent R2, R3 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR9R10)t(C3-C10 cycloalkyl), xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer from 0 to 3, said alkyl group optionally contains 1 hetero moiety selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer ranging from 0 to 2, and xe2x80x94N(R9)xe2x80x94; said cycloalkyl, aryl and heterocyclic R3 groups are optionally fused to a benzene ring, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the foregoing R3 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 must be attached through a carbon atom unless R3 is H; each R4 is independently H or C1-C6 alkyl; each R6 is independently C1-C4 alkyl, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), xe2x80x94NR9(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; said alkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94NR9SO2R11, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94OR7, and C1-C4 alkyl; each R7 is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; the foregoing R7 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy; each R9 and R10 are independently H, C1-C4 alkyl; R11 is selected from R7 except H; R12 is C1-C4 alkyl except that R12 cannot be methyl if (a) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z2 is xcex2-OH, or if (b) X is OH, Y is O, W1 is H, W2 is xcex1-OH, Z1 is H, Z is H.
In a fourteenth preferred embodiment of the compound of formula 1:
V is R3OC(O), R3R4NC(O) or R3O(R4)NC(O) and the preferred configuration of the 1xe2x80x3 center is that of hygromycin A.
In a fifteenth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the fourteenth preferred embodiment, but:
X is F, H or OH;
Y is O;
W1 is R3, W2 is OR13; or W1 is H, W2 is R3 or F; Z1 is R3, Z2 is OR13; or Z is H, Z2 is R3 or F; wherein each R3 and R13 are independently H or C1-C4 alkyl, and said alkyl groups are optionally substituted by 1 to 3 R6 groups; wherein each R6 is independently halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, or xe2x80x94NR7R9; wherein each R7 and R9 are independently H or C1-C4 alkyl; R11 is C1-C4 alkyl;
within substituent V, R3 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR9R10)t(C3-C10 cycloalkyl), xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer ranging from 0 to 3, said alkyl group optionally contains 1 hetero moiety selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer ranging from 0 to 2, and xe2x80x94N(R9)xe2x80x94; said cycloalkyl, aryl and heterocyclic R3 groups are optionally fused to a benzene ring, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the foregoing R3 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 must be attached through a carbon atom unless R3 is H; each R4 is independently H or C1-C6 alkyl; each R6 is independently C1-C4 alkyl, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), xe2x80x94NR9(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; said alkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94NR9SO2R11, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94OR7, C1-C4 alkyl; R7 is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; the foregoing R7 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy; each R9 and R10 are independently H and C1-C4 alkyl; R11 is selected from R7 except H.
In a sixteenth preferred embodiment of the compound of formula 1:
V is a moiety of the structure 
xe2x80x83and the preferred configuration of the 1xe2x80x3 center is that of hygromycin A.
In a seventeenth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the sixteenth preferred embodiment, but:
X is F, H or OH;
Y is O;
W1 is R3, W2 is OR13; or W1 is H, W2 is R3 or F; Z1 is R3, Z2 is OR13; or Z1 is H, Z2 is R3 or F; wherein each R3 and R13 are independently H or C1-C4 alkyl, and said alkyl groups are optionally substituted by 1 to 3 R6 groups; wherein each R6 is independently halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR , xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, or xe2x80x94NR7R9; wherein each R7 and R9 is H or C1-C4 alkyl; R11 is C1-C4 alkyl;
within the substituent V, R3 is C1-C6 alkyl; each R13 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR9R10)t(C3-C10 cycloalkyl), xe2x80x94(CR9R10)t(C6-C10 aryl), and xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer ranging from 0 to 3, said alkyl group optionally contains 1 hetero moiety selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer ranging from 0 to 2, and xe2x80x94N(R9)xe2x80x94; said cycloalkyl, aryl and heterocyclic R3 groups are optionally fused to a benzene ring, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the foregoing R3 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 5 R6 groups, and with the proviso that R3 must be attached through a carbon atom unless R3 is H; each R6 is independently C1-C4 alkyl, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), xe2x80x94NR9(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; said alkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94NR9SO2R11, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94OR7, and C1-C4 alkyl; each R7 is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; the foregoing R7 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy; each R9 and R10 are independently H or C1-C4 alkyl; R11 is selected from R7 except H.
In a eighteenth preferred embodiment of the compound of formula 1:
V is a group of the structure 
xe2x80x83where both E and Z isomers are included and the preferred configuration of the 1xe2x80x3 center is that of hygromycin A.
In a nineteenth preferred embodiment of the compound of formula 1:
the preferred groups as indicated for the eighteenth preferred embodiment, but:
X is F, H or OH;
Y is O;
R13 is xe2x80x94(CR9R10)t(C6-C10 aryl) or xe2x80x94(CR9R10)t(4 to 10 membered heterocyclic), wherein each t is independently an integer ranging from 0 to 2, and the foregoing R3 groups are optionally substituted by 1 to 5 R6 groups; wherein each R6 is independently C1-C4 alkyl, oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, (CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), or xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; said alkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94OR7, and C1-C4 alkyl; each R7 is independently selected from H and C1-C4 alkyl; the foregoing R7 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from trifluoromethyl, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, and C1-C4 alkoxy; each R9 and R10 are independently H or C1-C4 alkyl;
each R4 and R14 are independently selected from H and C1-C4 alkyl;
R3 is C1-C4 alkyl, and said alkyl group is optionally substituted by 1 to 3 R6 groups; each R6 is independently selected from C1-C4 alkyl, oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9SO2R11, xe2x80x94SO2NR7R9, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94S(O)j(CR9R10)m(C6-C10 aryl), xe2x80x94S(O)j(C1-C6 alkyl), wherein j is an integer ranging from 0 to 2, xe2x80x94(CR9R10)m(C6-C10 aryl), xe2x80x94O(CR9R10)m(C6-C10 aryl), xe2x80x94NR9(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; and said alkyl, cycloalkyl, aryl and heterocyclic R6 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94NR9SO2R11, xe2x80x94C(O)R7, xe2x80x94NR9C(O)OR11, xe2x80x94NR9C(O)R7, xe2x80x94C(O)NR7R9, xe2x80x94NR7R9, xe2x80x94OR7, C1-C4 alkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; each R7 is independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, xe2x80x94(CR9R10)m(C6-C10 aryl), and xe2x80x94(CR9R10)m(4 to 10 membered heterocyclic), wherein each m is independently an integer ranging from 0 to 2; said alkyl group optionally includes 1 hetero moiety selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer ranging from 0 to 2, and xe2x80x94N(R9)xe2x80x94; said cycloalkyl, aryl and heterocyclic R7 groups are optionally fused to a C6-C10 aryl group, a C5-C8 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the foregoing R7 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, xe2x80x94C(O)R9, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy, and with the proviso that R7 must be attached through a carbon atom unless R7 is H; each R9 and R10 are independently H or C1-C4 alkyl.
In a twentieth preferred embodiment of the compound of formula 1:
V is a carbon-linked 4 to 10 membered heterocyclic group, which may be optionally substituted by 1 to 3 R6 groups and the preferred configuration of the 1xe2x80x3 center is that of hygromycin A.
Specific preferred compounds of formula 1 include those listed below as well as the pharmaceutically acceptable salts, solvates and prodrugs of the following compounds:
1. 3-(3-Fluoro-4-((2S,4S,5R)-4-hydroxy-5-(1-methoxyimino-2-phenoxy-ethyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
2. 3-(4-((2S,4S,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-2-hydroxy-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
3. 3-(4-((2S,3S,4S,5R)-5-(5R-(3-Chloro-phenyl)-2,3-dimethyl-isoxazolidin-3-yl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
4. (2S,3S,5S)-5-(2-Fluoro-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-propenyl)-phenoxy)-3-hydroxy-tetrahydro-furan-2-carboxylic acid benzyloxy-amide
5. 3-(4-((2S,4S,5R)-5-(((E)-2-Fluoro-4-chloro-benzyloxyimino)-methyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
6. (2S,3S,4S,5S)-3,4-Dihydroxy-5-(2-hydroxy-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-propenyl)-phenoxy)-tetrahydro-furan-2-carboxylic acid benzyloxy-amide
7. (2S,3S,5S)-5-(2-Fluoro-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-propenyl)-phenoxy)-3-hydroxy-tetrahydro-furan-2-carboxylic acid benzylamide
8. 3-(4-((2R,4S,5S)-5-(1-((E)-2-Fluoro-4-chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
9. 3-(4-((2S,3S,5S)-5-(1-((E)-2,4-Dichloro-benzyloxyimino)-ethyl)-3-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
10. 3-(4-((2R,4S,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
11. 3-(4-((2S,3S,5S)-5-(1-((E)-3,4-Difluoro-benzyloxyimino)-ethyl)-3-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
12. 3-(4-((2S,5S)-5-(1-((E)-2-Chloro-5-fluoro-benzyloxyimino)-ethyl)-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
13. 3-(4-((2R,4S,5R)-5-(1-((E)-2,4-Dichloro-5-fluoro-benzyloxyimino)-ethyl)-4-methoxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
14. 3-(4-((2S,3S,4S,5R)-3-Amino-5-(1-((E)-3-chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
15. 3-(4-((2S,4S,5S)-5-(1-(3-Chloro-benzyloxy)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-3-(4-((2S,4R,5R)-5-(1-((E)-2-Chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
16. 3-(4-((2S,4S,5R)-5-(1-((E)-Benzo(1,3)dioxol-5-ylmethoxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
17. 3-(4-((1R,3R,4R)-3-(1-((E)-Benzo(1,3)dioxol-5-ylmethoxyimino)-ethyl)-4-hydroxy-cyclopentyloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
18. 3-(4-((1R,3R,4R)-3-(((E)-Benzo(1,3)dioxol-5-ylmethoxyimino)-methyl)-4-hydroxy-cyclopentyloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
19. 3-(4-((2S,4S,5R)-5-(1-((E)-Benzo[1,3)dioxol-5-ylmethoxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
20. 3-(4-((2S,4S,5R)-5-(((E)-Benzo(1,3)dioxol-5-ylmethoxyimino)-methyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
21. 3-(4-((1R,2S,3R,4R)-4-(((E)-2,4-Dichloro-benzyloxyimino)-methyl)-2,3-dihydroxy-cyclopentyloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
22. 3-(4-((1S,3R,4R)-3-(1-((E)-2,3-Dichloro-5-fluoro-benzyloxyimino)-ethyl)-4-hydroxy-cyclopentyloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
23. 3-(4-((1R,2S,4R)-4-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-2-hydroxy-cyclopentyloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
24. 3-(4-((1S,3R)-3-(1-((E)-3,4-Difluoro-benzyloxyimino)-ethyl)-cyclopentyloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
25. 3-(4-((1R,2S,3R,4R)-4-(1-((E)-2-Fluoro-benzyloxyimino)-ethyl)-2,3-dihydroxy-cyclopentyloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
26. 3-(4-((2S,3S,4S,5S)-5-(1-(3-Chloro-benzylideneaminooxy)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
27. 3-(4-((2S,4S,5S)-5-(1-(1-(4-Fluoro-phenyl)-ethylideneaminooxy)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
28. 3-(4-((2S,4S,5S)-5-(1-(1-(2,4-Dichloro-phenyl)-ethylideneaminooxy)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
29. 3-(4-((2S,3S,4S,5R)-5-(2-(2,4-Dichloro-benzyl)-thiazol4-yl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
30. 3-(4-((2S,3S,4S,5R)-5-(3-(2,4-Dichloro-phenoxy)-1-hydroxymethyl-(E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
31. 3-(4-((2S,4S,5R)-5-(3-(2,4-Dichloro-phenoxy)-1-hydroxymethyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
32. 3-(4-((1R,2S,3R,4S)-4-(3-(2,4-Dichloro-phenoxy)-(E)-propenyl)-2,3-dihydroxy-cyclopentyloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
33. 3-(4-(2S,3S,4S,5R)-5-(2-(2,4-Dichloro-benzyl)-3H-imidazol4-yl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
34. 3-(4-((2S,3S,4S,5R)-5-(6-Chloro-1H-benzoimidazol-2-yl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
35. 3-(4-((2S,3S,4S,5R)-5-(1-(Nxe2x80x2-(2,4-Dichloro-benzylidene)-hydrazino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yioxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
36. 3-(4-((2S,3S,4S,5R)-5-(1-(Nxe2x80x2-(2-Chloro-benzylidene)-hydrazino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
37. 3-(4-((2S,4S,5R)5-(1-(Nxe2x80x2-(2-Chloro-5-fluoro-benzylidene)-hydrazino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
38. 3-(4-((2S,4S,5R)-5-(1-(Nxe2x80x2-(3-Chloro-benzylidene)-hydrazino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
39. 3-(4-((2S,4S,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
40. 3-(4-((2S,3R,4S,5R)-5-(1-((E)-2,3-Dichloro-5-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
41. 3-(4-((2S,3R,4S,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
42. 3-(4-((2S,4S,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
43. 3-(4-((2S,4S,5R)-5-((E)-1-Benzyloxyimino-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
44. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
45. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-3,4-Difluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
46. 3-(4-((2S,3R,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
47. 3-(3-Fluoro-4-((2S,4S,5R)-5-(1-((E)-3-fluoro-4-morpholin-4-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
48. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((E)-4-fluoro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
49. 3-(4-((2S,4S,5R)-5-(3-(2,4-Dichloro-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
50. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(2-chloro-5-fluoro-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
51. 3-(3-Amino-4-((2S,3R,4S,5R)-5-(1-((E)-2-chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
52. 3-(4-((2S,3R,4S,5R)-5-(3-(2-Fluoro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
53. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(3-chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
54. 3-(4-((2S,3R,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
55. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
56. 3-(4-((2S,3R,4R,5R)-5-(3-(3,4-Difluoro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
57. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(2-fluoro-4-chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
58. 3-(4-((2S,4S,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
59. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((E)-2,4-dichloro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
60. 3-(4-((2S,4S,5R)-5-(3-(3-Chloro-phenoxy)-1-ethyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
61. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(2,3-dichloro-5-fluoro-phenoxy)-1-ethyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
62. 3-(3-Amino-4-((2S,4S,5R)-5-((E)-1-benzyloxyimino-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
63. 3-(3-Fluoro-4-((2S,4S,5R)-4-hydroxy-5-(1-methyl-3-phenoxy-(E)-propenyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
64. 3-(3-Amino-4-((2S,4S,5R)-4-hydroxy-5-(1-methyl-3-phenoxy-(E)-propenyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
65. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-2-Chloro-5-fluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
66. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(1-((E)-2-chloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
67. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
68. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(3-(2-fluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
69. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-propyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
70. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-propyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
71. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-ethyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
72. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-ethyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
73. 3-(4-((2S,3R,4R,5R)-5-(1-((E)-3,4-Difluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
74. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(1-((E)-2,3-dichloro-5-fluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
75. 3-(4-((2S,3R,4R,5R)-5-(3-(2-Chloro-5-fluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
76. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(2-fluoro-4-chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
77. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((E)-3-fluoro-4-morpholin-4-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
78. 3-(3-Fluoro-4-((2S,4S,5R)-5-(3-(3-fluoro-4-morpholin-4-yl-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
79. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(3-fluoro-4-morpholin-4-y-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
80. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
81. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-2-Fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R 5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
82. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
83. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
84. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(3-(3-chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
85. 3-(4-((2S,3S,5S)-5-(1-((E)-2,4-Dichloro-benzyloxyimino)-ethyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
86. 3-(4-((2S,3S,5S)-5-(3-(3,4-Difluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
87. 3-(4-((2S,3S,5S)-5-(1-((E)-2-Chloro-benzyloxyimino)-ethyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
88. 3-(4-((2S,3S,5S)-5-(3-(2-Fluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
89. 3-(4-((2S,3R,5S)-5-(1-((E)-2-Fluoro-4-chloro-benzyloxyimino)-ethyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
90. 3-(4-((2S,3R,5S)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
91. 3-(4-((2S,3R,5S)-5-(1-((E)-2-Chloro-5-fluoro-benzyloxyimino)-ethyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
92. 3-(4-((2S,3R,5S)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
93. 3-(4-((2S,3R,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
94. 3-(4-((2S,4S,5R)-5-(3-(3,4-Difluoro-phenoxy)-1-ethyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
95. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Chloro-5-fluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
96. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Fluoro-4-chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
97. 3-(4-((2S,3R,4R,5R)-5-(3-(2,4-Dichloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
98. 3-(4-((2S,4S,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
99. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(2-chloro-phenoxy)-1-methyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
100. 3-(4-((2S,3R,4S,5R)-5-(3-(2-Fluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
101. 3-(3-Amino-4-((2S,3R,4S,5R)-5-(3-(3-chloro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
102. 3-(4-((2S,3R,4R,5R)-5-(3-(3,4-Difluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
103. 3-(4-((2S,3R,4R,5R)-5-(3-(4-Fluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
104. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(2-fluoro-4-chloro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
105. 3-(4-((2S,4S,5R)-5-(3-(3-Chloro-phenoxy)-1-ethyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
106. 3-(4-((2S,4S,5R)-5-(3-(2,3-Dichloro-5-fluoro-phenoxy)-1-ethyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
107. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(2-fluoro-phenoxy)-1-ethyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
108. 3-(3-Fluoro-4-((2S,4S,5R)-4-hydroxy-5-(1-methyl-3-phenoxy-(Z)-propenyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
109. 3-(3-Amino-4-((2S,4S,5R)-4-hydroxy-5-(1-methyl-3-phenoxy-(Z)-propenyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
110. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Chloro-5-fluoro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
111. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
112. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(3-(2,4-dichloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
113. 3-(4-((2S,3S,4R,5R)-5-(3-(3,4-Difluoro-phenoxy)-1-ethyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
114. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Chloro-phenoxy)-1-ethyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
115. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Fluoro-4-chloro-phenoxy)-1-ethyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
116. 3-(4-((2S,3R,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
117. 3-(4-((2S,3R,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
118. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(2,4-dichloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
119. 3-(3-Fluoro-4-((2S,4S,5R)-5-(3-((E)-3-fluoro-4-morpholin-4-yl-phenoxy)-1-methyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
120. 3-(3-Amino-4-((2S,4S,5R)-5-(3-((E)-3-fluoro-4-morpholin-4-yl-phenoxy)-1-methyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
121. 3-(4-((2S,3R,4S,5R)-3-Amino-5-(1-((E)-3,4-difluoro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
122. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
123. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(3-(4-fluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
124. 3-(4-((2S,3S,4S,5R)-5-(1-((E)-2-Fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
125. 3-(3-Amino-4-((2S,3S,4S,5R)-5-(1-((E)-2-chloro-5-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
126. 3-(4-((2S,3S,4S,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
127. 3-(3-Amino-4-((2S,3S,4S,5R)-5-(3-(2,4-dichloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
128. 3-(4-((2S,3S,4S,5R)-5-(3-(2-Fluoro-4-chloro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
129. 3-(3-Amino-4-((2S,3S,4S,5R)-5-(3-(3,4-difluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
130. 3-(4-((2S,3S,4S,5R)-5-(5S-(3-Chloro-phenyl)-2,3-dimethyl-isoxazolidin-3-yl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
131. 3-(4-((2S,4S,5R)-5-(1-((Z)-2-Chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
132. 3-(4-((2S,3R,4S,5R)-5-(1-((Z)-2,4-Dichloro-5-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-fu ran-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
133. 3-(4-((2S,3R,4S,5R)-5-(1-((Z)-2-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
134. 3-(4-((2S,4S,5R)-5-(1-((Z)-3,4-Difluoro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
135. 3-(4-((2S,4S,5R)-5-((Z)-1-Benzyloxyimino-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
136. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-2-Fluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
137. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-2,4-Dichloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
138. 3-(4-((2S,3R,4R,5R)-5-(1-((Z)-2,4-Dichloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
139. 3-(3-Fluoro-4-((2S,4S,5R)-5-(1-((Z)-3-fluoro-4-morpholin-4-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
140. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((Z)-2-fluoro-4-chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
141. 3-(4-((2S,3R,4R,5R)-5-(1-((Z)-2-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
142. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(1-((Z)-2-chloro-5-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
143. 3-(4-((2S,4S,5R)-5-(1-((Z)-3-Chloro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
144. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((Z)-3-Chloro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
145. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-2-Chloro-benzyloxyimino)-propyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
146. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-3-Chloro-benzyloxyimino)-propyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
147. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((Z)-3-fluoro-4-morpholin-4-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
148. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-2,4-Dichloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
149. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(1-((Z)-2-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
150. 3-(4-((2S,4S,5R)-5-(1-((E)-3,4-Difluoro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide.
151. 3-(4-((2S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
152. 3-(4-((2S,4R,5R)-5-(3-(2,4-Dichloro-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
153. 3-(3-Fluoro-4-((2S,4R,5R)-4-hydroxy-5-(1-((E)-4-piperidin-1-yl-benzyloxyimino)-ethyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
154. 3-(4-((2S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
155. 3-(3-Fluoro-4-((2S,4R,5R)-4-hydroxy-5-(1-((E)-4-morpholin-4-yl-benzyloxyimino)-ethyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
156. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-(4,6,7-trihydroxy-hexahydro-benzo[1,3]dioxol-5-yl)-(2E)-acrylamide
157. 3-(3-Fluoro-4-((2S,4R,5R)-5-(1-((E)-3-fluoro-4-piperidin-1-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
Additional preferred compounds of formula 1, which are more preferred than those referred to above, include those listed below as well as the pharmaceutically acceptable salts, solvates and prodrugs of the following compounds:
1. 3-(4-((2S,4S,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
2. 3-(4-((2S,3R,4S,5R)-5-(1-((E)-2,3-Dichloro-5-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
3. 3-(4-((2S,3R,4S,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
4. 3-(4-((2S,4S,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
5. 3-(4-((2S,4S,5R)-5-((E)-1-Benzyloxyimino-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
6. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
7. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-3,4-Difluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
8. 3-(4-((2S,3R,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
9. 3-(3-Fluoro-4-((2S,4S,5R)-5-(1-((E)-3-fluoro-4-morpholin-4-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
10. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((E)-4-fluoro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
11. 3-(4-((2S,4S,5R)-5-(3-(2,4-Dichloro-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
12. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(2-chloro-5-fluoro-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
13. 3-(3-Amino-4-((2S,3R,4S,5R)-5-(1-((E)-2-chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
14. 3-(4-((2S,3R,4S,5R)-5-(3-(2-Fluoro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
15. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(3-chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
16. 3-(4-((2S,3R,4R,5R)-5-(1-((E)-2-Fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
17. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
18. 3-(4-((2S,3R,4R,5R)-5-(3-(3,4-Difluoro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
19. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(2-fluoro-4-chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
20. 3-(4-((2S,4S,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
21. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((E)-2,4-dichloro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
22. 3-(4-((2S,4S,5R)-5-(3-(3-Chloro-phenoxy)-1-ethyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
23. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(2,3-dichloro-5-fluoro-phenoxy)-1-ethyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
24. 3-(3-Amino-4-((2S,4S,5R)-5-((E)-1-benzyloxyimino-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
25. 3-(3-Fluoro-4-((2S,4S,5R)-4-hydroxy-5-(1-methyl-3-phenoxy-(E)-propenyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
26. 3-(3-Amino-4-((2S,4S,5R)-4-hydroxy-5-(1-methyl-3-phenoxy-(E)-propenyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
27. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-2-Chloro-5-fluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
28. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(1-((E)-2-chloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
29. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
30. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(3-(2-fluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
31. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-propyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
32. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-propyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
33. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-ethyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
34. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-ethyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
35. 3-(4-((2S,3R,4R,5R)-5-(1-((E)-3,4-Difluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
36. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(1-((E)-2,3-dichloro-5-fluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
37. 3-(4-((2S,3R,4R,5R)-5-(3-(2-Chloro-5-fluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
38. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(2-fluoro-4-chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
39. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((E)-3-fluoro-4-morpholin-4-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
40. 3-(3-Fluoro-4-((2S,4S,5R)-5-(3-(3-fluoro-4-morpholin-4-yl-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
41. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(3-fluoro-4-morpholin-4-yl-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
42. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-4-Fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
43. 3-(4-((2S,3S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
44. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
45. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
46. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(3-(3-chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
47. 3-(4-((2S,3S,5S)-5-(1-((E)-2,4-Dichloro-benzyloxyimino)-ethyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
48. 3-(4-((2S,3S,5S)-5-(3-(3,4-Difluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
49. 3-(4-((2S,3S,5S)-5-(1-((E)-2-Chloro-benzyloxyimino)-ethyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
50. 3-(4-((2S,3S,5S)-5-(3-(2-Fluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
51. 3-(4-((2S,3R,5S)-5-(1-((E)-2-Fluoro-4-chloro-benzyloxyimino)-ethyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
52. 3-(4-((2S,3R,5S)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
53. 3-(4-((2S,3R,5S)-5-(1-((E)-2-Chloro-5-fluoro-benzyloxyimino)-ethyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
54. 3-(4-((2S,3R,5S)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
55. 3-(4-((2S,3R,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
56. 3-(4-((2S,4S,5R)-5-(3-(3,4-Difluoro-phenoxy)-1-ethyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
57. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Chloro-5-fluoro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
58. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Fluoro-4-chloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
59. 3-(4-((2S,3R,4R,5R)-5-(3-(2,4-Dichloro-phenoxy)-1-methyl-(E)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
60. 3-(4-((2S,4S,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
61. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(2-chloro-phenoxy)-1-methyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
62. 3-(4-((2S,3R,4S,5R)-5-(3-(2-Fluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
63. 3-(3-Amino-4-((2S,3R,4S,5R)-5-(3-(3-chloro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
64. 3-(4-((2S,3R,4R,5R)-5-(3-(3,4-Difluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
65. 3-(4-((2S,3R,4R,5R)-5-(3-(4-Fluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
66. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(2-fluoro-4-chloro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
67. 3-(4-((2S,4S,5R)-5-(3-(3-Chloro-phenoxy)-1-ethyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
68. 3-(4-((2S,4S,5R)-5-(3-(2,3-Dichloro-5-fluoro-phenoxy)-1-ethyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
69. 3-(3-Amino-4-((2S,4S,5R)-5-(3-(2-fluoro-phenoxy)-1-ethyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
70. 3-(3-Fluoro-4-((2S,4S,5R)-4-hydroxy-5-(1-methyl-3-phenoxy-(Z)-propenyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
71. 3-(3-Amino-4-((2S,4S,5R)-4-hydroxy-5-(1-methyl-3-phenoxy-(Z)-propenyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
72. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Chloro-5-fluoro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
73. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
74. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(3-(2,4-dichloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
75. 3-(4-((2S,3S,4R,5R)-5-(3-(3,4-Difluoro-phenoxy)-1-ethyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
76. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Chloro-phenoxy)-1-ethyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
77. 3-(4-((2S,3S,4R,5R)-5-(3-(2-Fluoro-4-chloro-phenoxy)-1-ethyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
78. 3-(4-((2S,3R,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
79. 3-(4-((2S,3R,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
80. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(3-(2,4-dichloro-phenoxy)-1-methyl-(Z)-propenyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
81. 3-(3-Fluoro-4-((2S,4S,5R)-5-(3-((E)-3-fluoro-4-morpholin-4-yl-phenoxy)-1-methyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
82. 3-(3-Amino-4-((2S,4S,5R)-5-(3-((E)-3-fluoro-4-morpholin-4-yl-phenoxy)-1-methyl-(Z)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
83. 3-(4-((2S,3R,4S,5R)-3-Amino-5-(1-((E)-3,4-difluoro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
84. 3-(4-((2S,3S,4R,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
85. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(3-(4-fluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
86. 3-(4-((2S,3S,4S,5R)-5-(1-((E)-2-Fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
87. 3-(3-Amino-4-((2S,3S,4S,5R)-5-(1-((E)-2-chloro-5-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
88. 3-(4-((2S,3S,4S,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
89. 3-(3-Amino-4-((2S,3S,4S,5R)-5-(3-(2,4-dichloro-phenoxy)-1-methyl-(E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
90. 3-(4-((2S,3S,4S,5R)-5-(3-(2-Fluoro-4-chloro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
91. 3-(3-Amino-4-((2S,3S,4S,5R)-5-(3-(3,4-difluoro-phenoxy)-1-methyl-(Z)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
92. 3-(4-((2S,4S,5R)-5-(1-((Z)-2-Chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
93. 3-(4-((2S,3R,4S,5R)-5-(1-((Z)-2,4-Dichloro-5-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
94. 3-(4-((2S,3R,4S,5R)-5-(1-((Z)-2-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
95. 3-(4-((2S,4S,5R)-5-(1-((Z)-3,4-Difluoro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
96. 3-(4-((2S,4S,5R)-5-((Z)-1-Benzyloxyimino-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
97. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-2-Fluoro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
98. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-2,4-Dichloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
99. 3-(4-((2S,3R,4R,5R)-5-(1-((Z)-2,4-Dichloro-benzyloxyimino)-ethyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
100. 3-(3-Fluoro-4-((2S,4S,5R)-5-(1-((Z)-3-fluoro-4-morpholin-4-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
101. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((Z)-2-fluoro-4-chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
102. 3-(4-((2S,3R,4R,5R)-5-(1-((Z)-2-Chloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
103. 3-(3-Amino-4-((2S,3R,4R,5R)-5-(1-((Z)-2-chloro-5-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
104. 3-(4-((2S,4S,5R)-5-(1-((Z)-3-Chloro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
105. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((Z)-3-Chloro-benzyloxyimino)-propyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
106. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-2-Chloro-benzyloxyimino)-propyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
107. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-3-Chloro-benzyloxyimino)-propyl)-3-fluoro-4-hydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
108. 3-(3-Amino-4-((2S,4S,5R)-5-(1-((Z)-3-fluoro-4-morpholin-4-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
40 109. 3-(4-((2S,3S,4R,5R)-5-(1-((Z)-2,4-Dichloro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
110. 3-(3-Amino-4-((2S,3S,4R,5R)-5-(1-((Z)-2-fluoro-benzyloxyimino)-ethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
111. 3-(4-((2S,4S,5R)-5-(1-((E)-3,4-Difluoro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
112. 3-(4-((2S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
113. 3-(4-((2S,4R,5R)-5-(3-(2,4-Dichloro-phenoxy)-1-methyl-(E)-propenyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-3-fluoro-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
114. 3-(4-((2S,4R,5R)-5-(1-((E)-3-Chloro-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
115. 3-(3-Fluoro-4-((2S,4R,5R)-4-hydroxy-5-(1-((E)-4-morpholin-4-yl-benzyloxyimino)-ethyl)-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
116. 3-(3-Fluoro-4-((2S,4R,5R)-5-(1-((E)-3-fluoro-4-piperidin-1-yl-benzyloxyimino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide
The invention also relates to a pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula 1, a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula 1, a prodrug thereof or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam, quinolone, tetracycline, streptogramin, aminoglycoside, glycopeptide, macrolide or oxazolidinone antibiotic; or in combination with a compound which inhibits bacterial or protozoal efflux or degradation of a compound according to formula 1.
The invention also relates to a method of treating a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula 1, a prodrug thereof or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of treating a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula 1, a prodrug thereof or a pharmaceutically acceptable salt thereof, in combination or co-administered with a beta-lactam, quinolone, tetracycline, streptogramin, aminoglycoside, glycopeptide, macrolide or oxazolidinone antibiotic; or in combination with a compound which inhibits bacterial or protozoal efflux or degradation of a compound according to formula 1.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
As used herein, unless otherwise indicated, the terms or phrases xe2x80x9cbacterial infection(s)xe2x80x9d, xe2x80x9cprotozoal infection(s)xe2x80x9d, and xe2x80x9cdisorders related to bacterial infections or protozoal infectionsxe2x80x9d include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. casselflavus, S. epidermidis, S. haemolyticus, or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebacterium diphtheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chiamydia pneumoniae; blood and tissue infections, including endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E. faecalis, E. faecium, E. durans, including strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracylines and macrolides; uncomplicated skin and soft tissue infections and abscesses, and puerperal fever related to infection by Staphylococcus aureus, coagulase-negative staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (minute-colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus aureus, coagulase-negative staphylococcal species, or Enterococcus spp.; urethritis and cervicitis; sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chiamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; infections caused by Mycobacterium tuberculosis, M. leprae, M. paratuberculosis, M. kansasii, or M. chelonei; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis or cardiovascular disease related to infection by Helicobacter pylori or Chiamydia pneumoniae. Bacterial infections and protozoal infections, and disorders related to such infections, which may be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. haemolytica, P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by protozoa (i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by S. aureus, Strep uberis, Streptococcus agalactiae, Streptococcus dysgalactiae, Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by A. pleuro., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by Lawsonia intracellularis, Salmonella, or Serpulina hyodysinteriae; cow footrot related to infection by Fusobacterium spp; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow pink-eye related to infection by Moraxella bovis; cow premature abortion related to infection by protozoa (i.e. neosporium); skin and soft tissue infections in dogs and cats related to infection by S. epidermidis, S. intermedius, coagulase neg. Staphylococcus or P. multocida; and dental or mouth infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and protozoal infections, and disorders related to such infections, which may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford et al., xe2x80x9cThe Sanford Guide To Antimicrobial Therapy,xe2x80x9d 26th Edition, (Antimicrobial Therapy, Inc., 1996).
The compounds of the present invention may be active against the bacteria and protozoa, and associated conditions, referred to above, or specific strains of the bacteria and protozoa referred to above.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro and chloro.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties. It is understood that for said alkyl group to include cyclic moieties it must contain at least three carbon atoms.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, includes alkyl groups, as defined above, having at least one carbon-carbon double bond.
The term xe2x80x9calkynylxe2x80x9d, as used herein, unless otherwise indicated, includes alkyl groups, as defined above, having at least one carbon-carbon triple bond.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term xe2x80x9c4 to 10 membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl and an example of a membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). The terms xe2x80x9c5 to 12 membered heterocyclicxe2x80x9d, xe2x80x9c5 to 6 membered heterocyclicxe2x80x9d, and other uses of xe2x80x9cheterocyclicxe2x80x9d, correspond to the above definition with an appropriate number of ring members.
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds of the present invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
The compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them. In this regard, the invention includes both the E and Z configurations of the xe2x80x94OR3 group connected to the nitrogen where R1 and R2 are taken together as an oxime moiety of the formula xe2x95x90Nxe2x80x94OR3. The invention also includes both E and Z configurations of the R5 and X1xe2x80x94X2xe2x80x94R8 groups connected to cargon where R1 and R2 are taken together as xe2x95x90C(R5)X1xe2x80x94X2xe2x80x94R8. The compounds of formula 1 may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The subject invention also includes isotopically-labelled compounds, and the pharmaceutically acceptable salts thereof, which are identical to those recited in formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula 1 of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
This invention also encompasses pharmaceutical compositions containing and methods of treating bacterial infections through administering prodrugs of compounds of the formula 1. Compounds of formula 1 having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula 1. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
Selective introduction of prodrug side chains can be carried out on the hydroxy groups of the hygromycin A core molecule. For instance, exhaustive silylation of the six hydroxy groups of hygromycin A can be carried out, for instance with tert-butyl dimethylsilyl chloride. Subjection of the hexasilyl derivative to the action of potassium carbonate in methanol at room temperature selectively removes the phenolic silyl group, allowing further selective modification at that position. In another example, incomplete silylation of hygromycin A provides the pentasilyl derivative in which the C-2xe2x80x3 hydroxy group of the furanose ring is free. Selective acylation, alkylation, etc. can be carried out on this derivative to provide prodrug attachment at C-2xe2x80x3, followed by elaboration to the compounds of formula 1.
Selective introduction of prodrug side chains onto the Fragment C moiety may be carried out by functionalizing Fragment C (Scheme 1) prior to coupling with fragments B and A, or by utilizing selective protection strategies after assembly of the three fragments.
Selective introduction of prodrug side chains onto the hydroxyl groups of the inositol sugar can be carried out through total synthesis of the inositol (Fragment A in Scheme 1). Adaptation of the chemistry published by Chida (J. Org. Chem., 1991, 56, 2976), Arjona (Tetrahedron Lett., 1995, 36, 1319 and Dudash (Dissertation, Stanford Univ., 1998, Diss. Abstr. Int., B, 1998, 59, 2754) allows selective addition of a prodrug onto the hydroxyl group of choice through use of selectively protected intermediates described in these reports. The inositol derivative bearing the prodrug is then appended to fragments B and C as described below.